Submissions for variant NM_002691.4(POLD1):c.378C>T (p.Arg126=)

gnomAD frequency: 0.00188  dbSNP: rs145324823

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001079436	SCV000262329	benign	Colorectal cancer, susceptibility to, 10	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000759962	SCV000518018	likely benign	not provided	2021-06-02	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000427145	SCV000596491	likely benign	not specified	2016-07-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000570853	SCV000670887	likely benign	Hereditary cancer-predisposing syndrome	2015-07-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV000427145	SCV000806539	benign	not specified	2017-06-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000427145	SCV000889686	benign	not specified	2017-06-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000427145	SCV000918074	benign	not specified	2018-04-23	criteria provided, single submitter	clinical testing	Variant summary: POLD1 c.378C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0017 in 276646 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 119 fold above the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000759962	SCV001335080	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	POLD1: BP4, BP7
Sema4, Sema4	RCV000570853	SCV002534677	likely benign	Hereditary cancer-predisposing syndrome	2021-05-07	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000427145	SCV002551871	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001079436	SCV004016652	benign	Colorectal cancer, susceptibility to, 10	2023-07-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000759962	SCV004562347	likely benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000570853	SCV000788147	likely benign	Hereditary cancer-predisposing syndrome	2018-02-14	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356191	SCV001551289	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLD1 p.Arg126= variant was not identified in the literature nor was it identified in the Cosmic database. The variant was identified in dbSNP (ID: rs145324823) as "With other allele" and ClinVar (classified as benign by Invitae and one other clinical laboratory; and as likely benign by GeneDx, Ambry Genetics, and two other clinical laboratories). The variant was identified in control databases in 468 of 276646 chromosomes (2 homozygous) at a frequency of 0.002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 5 of 23978 chromosomes (freq: 0.0002), Other in 12 of 6456 chromosomes (freq: 0.002), Latino in 69 of 34412 chromosomes (freq: 0.002), European in 252 of 126308 chromosomes (freq: 0.002), Finnish in 128 of 25720 chromosomes (freq: 0.005), and South Asian in 2 of 30782 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish or East Asian populations. The p.Arg126= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics, Academic Medical Center	RCV000759962	SCV001920082	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000759962	SCV001970952	likely benign	not provided		no assertion criteria provided	clinical testing